Pharmaceutical composition for treating dysmenorrhea and premature labor

ABSTRACT

The present invention teaches a composition comprising a β-adrenergic agonist in a bioadhesive carrier. Preferably, the composition comprises terbutaline in polycarbophil. The present invention additionally teaches the local administration of a β-adrenergic agonist for the purpose of treating or preventing dysmenorrhea or premature labor. Using this composition and the method of treatment provides sufficient local levels of the drug to provide therapeutic efficacy, but avoids many untoward adverse events.

[0001] This application claims the benefit of U.S. ProvisionalApplication No. 60/058,789, filed Sep. 12, 1997, which is incorporatedherein by reference.

FIELD OF THE INVENTION

[0002] The invention relates to a pharmaceutical composition and thelocal administration thereof for the purpose of treating or preventingdysmenorrhea or premature labor.

BACKGROUND OF THE INVENTION

[0003] Both dysmenorrhea and premature labor affect significant numbersof American women; however, treatment regimens are still lacking forboth conditions. Dysmenorrhea, menstrual cramps, affects on average over50% of women and results in frequent absenteeism or loss of activity.Andersch, B., Milsom I., An Epidemiologic study of young women withdysmenorrhea, A.J.O.G., 144:655-60 (1982). Young women report a somewhathigher incidence of dysmenorrhea than the average, with estimatesranging from 67% to 72%. Harlow, S. D., Parck M., A longitudinal studyof risk factors for the occurrence, duration and severity of menstrualcramps in a cohort of college women, Br. J. Obstet. Gynaecol.,103:1134-42 (1996). Severe pain has been reported by 7 to 15% of women.Id.

[0004] In the United States alone an estimated 140 million work andschool hours are lost per year due to this condition. Klein, J. R.,Litt, I. F., Epidemiology of adolescent dysmenorrhea, Pediatrics,68:6661-64 (1981). About 42% of United States university studentsbetween the ages of 17 and 19 have had to be absent from their dailyactivities at least once due to dysmenorrhea. Id. Approximately 15% ofyoung women have one to three days of incapacitation each month anddysmenorrhea is the leading cause of short-term school absenteeism amongadolescent young women. Id. This disease, with its constant regularity,results in notable social, educational, and economic losses in thiscountry.

[0005] Dysmenorrhea consists of painful uterine cramping and is oftenaccompanied by associated symptoms including nausea, vomiting, diarrhea,and lower backaches. Treatments for dysmenorrhea currently focus on theuse of non-steroidal antiinflammatory drugs (NSAIDs). These drugsinclude, for instance, naproxen, ibuprofen, mefenamic acid, andmeclofenamate sodium. Oral contraceptives are also used by some women inthe treatment of dysmenorrhea. Despite the fact that these two regimenscan be used together, the recurring problems of dysmenorrhea have notbeen eliminated for many women.

[0006] Specifically, the painful uterine cramping associated withdysmenorrhea is probably triggered by vasopressin and increasedproduction of prostaglandins. The current method of treatment, withNSAIDs, blocks prostaglandin production and acts as a painkiller.Although this method of treatment is effective in some women anddecreases symptoms in other women, researchers have wondered whetherblocking the dysmenorrheic process at an earlier step would provide moreeffective treatment in the prevention of uterine cramping.

[0007] Although no link has formally been established, some researchersbelieve that untreated dysmenorrhea may play a role in the genesis ofsuch serious clinical conditions as endometriosis. Recent studies haveshown that endometriosis is associated with dyskinetic patterns ofuterine contractions at the time of menses. Salamanca, A., Beltran, E.,Subendometrial Contractility in Menstrual Phase Visualized byTransvaginal Sonography in Patients with Endometriosis. Fertil. Steril.,65:193-95 (1995). Additionally, the symptoms of dysmenorrhea can oftenmask the more serious disease of endometriosis. Symptoms of dysmenorrheaoften occur in women with endometriosis for nearly ten years on averageprior to laproscopic diagnosis of the later disease. Hadfield, R.,Mardon, H., Barlow, D., Kennedy, S., Delay in the Diagnosis ofEndometriosis: A Survey of Women from the U.S.A. and U.K. Human Reprod.,11:878-80 (1996).

[0008] Premature labor also affects a significant number of women in theUnited States.

[0009] Preterm delivery is defined as delivery prior to 30 weeks ofgestation. This phenomenon complicates 8 to 10% of births in the UnitedStates and is a leading cause of neonatal morbidity and mortality.Lockwood, C. J., The diagnosis of PTL and the prediction of pretermdelivery, Clinical Obstetrics and Gynecology, Pitkin, R. M., Scott, J.R. (eds.), 38:675-678 (1995). In fact, prematurity causes 75% ofperinatal deaths in this country. McCombs, J., Update on TocolyticTherapy, Annals of Pharmacotherapy, 29:515-522 (1995). Premature infantsalso have an increased risk of other serious conditions, includingrespiratory distress syndrome, hyaline membrane disease, intracranialintraventricular hemorrhage, necrotizing enterocolitis, sepsis, and havean increased incidence of cerebral palsy. Id.

[0010] Currently, preventing preterm delivery focuses on the earlydiagnosis of impending premature labor in women with intact membranes.Oral tocolytic agents, or uterine relaxants, are the treatment ofchoice. Tocolytic agents include progestational compounds, β-adrenergicagonists, NSAIDs, calcium agonists, oxytocin, or vasopressin agonists,and potassium channel openers. The most widely used of these are theβ-adrenergic agonists such as terbutaline and ritodrine. It should benoted, however, that of the β-adrenergic agonists, only ritodrine isapproved by the F.D.A. for use in preterm labor. Other β-adrenergicagonists, such as terbutaline, are approved for other conditions (e.g.,asthma) but have been used by practitioners in the treatment ofpremature labor. As these drugs are given orally, however, treatment isaccompanied by serious side effects. Research has failed to produce aβ-adrenergic agonist that is selective for the receptors in the uterusand consequently lacking of some of the most serious adverse events.

[0011] Terbutaline is a β-adrenergic agonist. Its chemical formula is5-[2-[(1,1-dimethylethyl)amino]-1-hydroxyethyl]-1,3-benzenediol. Theempirical formula of terbutaline is C₁₂H₁₉NO₃. Its molecular weight is225.29. Its structural formula is as follows:

[0012] Terbutaline, as a β-adrenergic agonist, has been used primarilyas a bronchodilator. β-adrenergic agonists exert their pharmacologiceffects by activation of adenyl cyclase, the enzyme that catalyzes theconversion of adenosine triphosphate (ATP) to cyclic adenosinemonophosphate (cAMP). Activation of adenyl cyclase by β-adrenergicagonists increases intracellular levels of cAMP. Cyclic AMP in turnreduces the availability of intracellular free Ca²⁺, which is requiredfor the activation of myosin light-chain kinase, the enzyme thatphosphorylates myosin and thereby allows it to combine with actin toform actomyosin. Lack of Ca²⁺ results in disruption of the actin-myosininteraction, with resultant inhibition of smooth muscle contractility.Due to their direct effects on smooth muscle contractility, β-adrenergicagonists, such as terbutaline, may prove to be an effective therapy forboth dysmenorrhea and premature labor.

[0013] In fact, oral and intravenous terbutaline has been used as areasonably effective therapy for preterm labor. Studies have shown thatoral or IV therapy can stop contractions or postpone delivery. Lyrenas,S., Grahnen, A., Lindberg, B., et. al., Pharmacokinetics of TerbutalineDuring Pregnancy, Eur. J. Clin. Pharmacol., 29:619-623 (1986); Berg.,G., Lindberg, C., Ryden G., Terbutaline in the Treatment of PretermLabour, Eur. J. Respir. Dis., 65:219-230 (1984). Adverse events canpresent significant problems in the treatment of preterm labor withterbutaline and are discussed further below.

[0014] A few studies also document the use of terbutaline in thetreatment of dysmenorrhea. In one study, treatment with IV terbutalineinhibited myometrial activity, increased blood flow to the uterus, andrelieved the pain occurring during uterine contractions accompanyingdysmenorrhea. Åkerlund, M., Andersson, K. E., and Ingemarsson, E.,Effects of Terbutaline on Myometrial Activity, Uterine Blood Flow, andLower Abdominal Pain in Women with Primary Dysmenorrhoea, Br. J. ofObstet. & Gyn., 83(9):673-78 (1976). Terbutaline inhalers have even beenevaluated for the treatment of dysmenorrhea. Kullander, S., Svanberg,L., Terbutaline Inhalation for Alleviation of Severe Pain in EssentialDysmenorrhea, Acta Obstet. Gynecol. Scand., 60:425-27 (1981). Thistherapy did provide some efficacy; however, treatment was not sufficientfor most patients, who had to supplement with other medications foradequate relief. Further, the effect of each spray lasted as little as 1hour. Id. One other β-adrenergic agonist, salambutol, showed pain reliefwhen administered intravenously. Lalos, O., Joelsson, I., Effect ofSalbutamol on the Non-Pregnant Human Uterus In Vivo, Acta Obstet.Gynecol. Scand., 60:349-52 (1981).

[0015] Several problems with administration and adverse effects,however, prevent women affected by dysmenorrhea and premature labor frombeing able to take full advantage of this therapy. First, β-adrenergicagonists such as terbutaline have a low bioavailability after oraladministration. These pharmaceuticals are well absorbed but haveextensive first-pass sulphation. Bioavailability has been estimated atbetween 15 and 20%. Concomitant food intake additionally decreasesbioavailability by a further 30%. Bricanyl: Scientific brochure, AstraFrance Laboratories (1993).

[0016] Second, adverse effects significantly limit the current utilityof terbutaline in the treatment of preterm labor and dysmenorrhea.Placental transfer of β-adrenergic agonists such as terbutaline isrelatively rapid; thus, adverse effects are observed in the fetus andneonate while treating premature labor using oral administration.Morgan, D. J., Clinical Pharmacokinetics of β-Agonists, Clin.Pharmacokin., 18:270-294 (1990). Thus, when treating preterm labor,adverse events can affect not only the woman but also her child.

[0017] The most serious adverse events are cardiovascular in nature.Intravenous administration of terbutaline has been associated withpalpitations and peripheral tremors. Åkerlund, M., Andersson, K. F.,Ingemarsson, I., Effects of Terbutaline on Myometrial Activity, UterineBlood Flow and Lower Abdominal Pain in Women With Primary Dysmenorrhea.Br. J. Obstet. Gyncol., 83:673-78 (1976). As a sympathomimetic amine,terbutaline can cause problems in patients with cardiovascular disorders(including arrhythmia, coronary insufficiency and hypertension), as wellas with patients with hyperthyroidism, diabetes mellitus, or a historyof seizures. Significant adverse reactions have been reported followingadministration of terbutaline to women in labor including pulmonaryedema and hypoglycemia in the mother and or neonate child. Intravenousterbutaline has also been reported to aggravate preexisting diabetes andketoacidosis. Other adverse events include: tremors, nervousness,increased heart rate, palpitations, and dizziness. Less frequent adverseeffects include headaches, drowsiness, vomiting, nausea, sweating,muscle cramps, and ECG changes.

[0018] These adverse effects have precluded the use of β-agonists suchas terbutaline to prevent or treat dysmenorrhea as it considered to be abenign or non-threatening condition. Åkerlund, M., Andersson, K. E., andIngemarsson, E., Effects of Terbutaline on Myometrial Activity, UterineBlood Flow, and Lower Abdominal Pain in Women with PrimaryDysmenorrhoea, Br. J. of Obstet. & Gyn., 83(9):673-78 (1976). Further,the risks involved have limited the use of these pharmaceutical agentsin the treatment of preterm delivery and premature labor as the benefitsmust be balanced carefully against the seriousness of the adverse eventsinvolved.

[0019] In an attempt to address the severity of the adverse eventsinvolved, researchers have been attempting to identify another effectivemeans for administering the drug that would decrease the risk involved.It is known that terbutaline can be administered directly to the uterus,resulting in preferential local concentrations as compared to peripheralcirculation concentrations. Kullander et al. studied the correlationbetween the uterine and blood concentrations of terbutaline afterinsertion of a terbutaline-impregnated polymer ring (10% terbutalinesulfate in a 5 g vaginal ring), terbutaline in a cellulose gel (0.1 mgin 1 mL cellulose gel), or a placebo ring in a patient 24 hours beforehysterectomy. Kullander, S., Svanberg, L., On resorption and the effectof vaginally administered terbutaline in women with premature labor.Acta. Obstet. Gynecol. Scand., 64:613-16 (1985). The methods followed inthis reference, however, have distinct disadvantages. The water solublecellulose-gel used can wash away and the use of a polymer ring can beuncomfortable and unpalatable for the woman, and thus both aredistinctly disadvantageous.

[0020] Other pharmaceutical compounds with problematic adverse eventshave been successfully administered locally. The bioadhesive carrier ofthe present invention has been used in other drug delivery systems,although with different results than in the present invention. Forexample, polycarbophil is a main ingredient in the vaginal moisturizerReplens®. It has also been used as a base for compositions with otheractive substances such as progesterone (Crinone®) (see U.S. Pat. No.5,543,150) and Nonoxynol-9 (Advantage-S) (see U.S. Pat. No. 5,667,492).

[0021] Additionally, it is important that pharmaceutical compositions donot interfere with all contractions and the homeostasis of menstruation.As menstrual blood does not clot, normal, regularized contractions arehelpful to stop the bleeding. If there are no contractions, then thepatient may not stop bleeding and may hemorrhage. Thus, it is an objectof the invention to interfere with the dyskinetic contractions causingdysmenorrhea, without stopping contractions entirely.

SUMMARY OF THE INVENTION

[0022] The present invention relates to a pharmaceutical compositioncomprising a therapeutically effective amount of a β-adrenergic agonisttogether with a pharmaceutically acceptable bioadhesive carrier and thelocal administration of β-adrenergic agonist for the purpose of treatingor preventing dysmenorrhea or premature labor. Using this compositionand the method of treatment provides sufficient local levels of the drugto provide therapeutic efficacy, but avoids many untoward adverseevents.

BRIEF DESCRIPTION OF THE DRAWINGS

[0023]FIG. 1 illustrates the serum terbutaline levels in a single dosestudy. Doses were 4 mg, 2 mg, and 1 mg. The terbutaline gel wasadministered transvaginally once.

[0024]FIG. 2 illustrates the serum terbutaline levels in a multiple dosestudy. Doses were 4 mg, 2 mg, and 1 mg. The terbutaline gel wasadministered transvaginally once daily for six days.

[0025]FIG. 3 illustrates the serum terbutaline levels in a single dosestudy. The dose given was 8 mg. The terbutaline gel was administeredtransvaginally once.

[0026]FIG. 4 illustrates the serum terbutaline levels in a multiple dosestudy. The dose given was 8 mg. The terbutaline gel was administeredtransvaginally once daily for six days.

[0027]FIG. 5 illustrates mean heart rates in a single dose study. Doseswere 8 mg, 4 mg, 2 mg, and 1 mg. The terbutaline gel was administeredtransvaginally once.

[0028]FIG. 6 illustrates mean heart rates in a multiple dose study.Doses were 8 mg, 4 mg, 2 mg, and 1 mg. The terbutaline gel wasadministered transvaginally once daily for six days.

[0029]FIG. 7 illustrates the myometrial terbutaline influx in an ex vivouterine perfusion model.

DETAILED DESCRIPTION OF THE INVENTION

[0030] The present invention is related to a composition comprisingtherapeutically effective amount of a β-adrenergic agonist together witha pharmaceutically acceptable bioadhesive carrier. Preferablyterbutaline is used as the β-adrenergic agonist. The present inventionpreferably comprises a β₂ specific adrenergic agonist. Other acceptableβ-adrenergic agonists include ritodrine, isoxsuprine, fenoterol,salambutol, hexoprenaline, metaproterenol, bitolterol and pirbuterol.The invention comprises a uterine smooth muscle relaxant for bothpregnant and non-pregnant women and has been specifically designed forvaginal administration. The bioadhesive carrier, which may be in a gelformulation, contains a polycarbophil base designed to give controlledand prolonged release of terbutaline, or another β-adrenergic agonist,through the vaginal mucosa. This route of administration avoidsfirst-pass metabolism problems. The direct delivery to the uterus allowsfor lower systemic drug concentrations. These two properties help avoidmany significant adverse events.

[0031] The present invention is additionally related to a method ofpreventing or treating dysmenorrhea comprising administering thecomposition vaginally. Additionally, the present invention includes amethod of preventing or treating premature labor comprisingadministering the composition vaginally. Most preferably, in preventingor treating both conditions, 1 to 1.5 g of the composition isadministered; although, acceptable amounts of the composition to beadministered include 0.5 to 2.5 g. The composition administered cancontain between 1 to less than about 8 mg of terbutaline per dose,preferably containing 1 to 4 mg, and most preferably containing 2 to 4mg. Dosages of 8 or more mg are not recommended, however, because sideeffects may be noted in some individuals at such levels. The compositioncan be administered every 12 to 48 hours, but is preferably administeredevery 24 hours. The composition can be administered during dysmenorrheaor optionally including one or more days prior to the anticipated onsetof dysmenorrhea. Similarly, the composition may be administered duringpremature labor or to prevent the onset of anticipated premature labor.

[0032] The present invention comprises a dosing regimen and manner oftreating dysmenorrhea. In practicing the invention, a patient need notwait until the onset of menses and the occurrence of pain to begintreatment. The present invention comprises administration of thecomposition as soon as the patient realizes that she is nearing theonset of menses, for example within a day or two. This method ofadministration is based on pharmacokinetic data below, and prevents theprocess of dyskinetic contractions from occurring, rather than treatingthem once the contractions have already begun.

[0033] Another important aspect of the invention is that theuterorelaxant formulation can correct dysmenorrhea and its dyskineticcontractions, without interfering with the normal contractions andbleeding during menstruation. Dysmenorrhea appears to involve dyskineticcontractions, which are erratic and abnormal. This is in contrast toother theories of dysmenorrhea as comprises solely an increase in theamplitude and frequency of contraction. The inventors believe that indysmenorrhea the nature of contractions change so that there are notonly antegrade contractions (fundus to cervix), but also retrogradecontractions (cervix to fundus), and non-functional fibrillations. Thecomposition of the present invention appears to provide relief by way ofa selective action on the dyskinetic contractions without preventing thenormal, regularized contractions necessary for menstruation.

[0034] The specific drug delivery formulation chosen and used in theexamples below comprises a cross-linked polycarboxylic acid polymerformulation, generally described in U.S. Pat. No. 4,615,697 to Robinson(hereinafter “the '697 patent”), which is incorporated herein byreference. In general, at least about eighty percent of the monomers ofthe polymer in such a formulation should contain at least one carboxylfunctionality. The cross-linking agent should be present at such anamount as to provide enough bioadhesion to allow the system to remainattached to the target epithelial surfaces for a sufficient time toallow the desired dosing to take place.

[0035] For vaginal administration, such as in the examples below,preferably the formulation remains attached to the epithelial surfacesfor a period of at least about twenty-four to forty-eight hours. Suchresults may be measured clinically over various periods of time, bytesting samples from the vagina for pH reduction due to the continuedpresence of the polymer. This preferred level of bioadhesion is usuallyattained when the cross-linking agent is present at about 0.1 to 6.0weight percent of the polymer, with about 1.0 to 2.0 weight percentbeing most preferred, as long as the appropriate level of bioadhesionresults. Bioadhesion can also be measured by commercially availablesurface tensiometers utilized to measure adhesive strength.

[0036] The polymer formulation can be adjusted to control the releaserate of the β-adrenergic agonist, such as terbutaline, by varying theamount of cross-linking agent in the polymer. Suitable cross-linkingagents include divinyl glycol, divinylbenzene, N,N-diallylacrylamide,3,4-dihydroxy-1,5-hexadiene, 2,5-dimethyl-1,5-hexadiene and similaragents.

[0037] A preferred polymer for use in such a formulation isPolycarbophil, U.S.P., which is commercially available from B. F.Goodrich Speciality Polymers of Cleveland, Ohio under the trade nameNOVEON®-AA1. The United States Pharmacopeia, 1995 edition, United StatesPharmacopeial Convention, Inc., Rockville, Md., at pages 1240-41,indicates that polycarbophil is a polyacrylic acid, cross-linked withdivinyl glycol.

[0038] Other useful bioadhesive polymers that may be used in such a drugdelivery system formulation are mentioned in the '697 patent. Forexample, these include polyacrylic acid polymers cross-linked with, forexample, 3,4-dihydroxy-1,5-hexadiene, and polymethacrylic acid polymerscross-linked with, for example, divinyl benzene.

[0039] Typically, these polymers would not be used in their salt form,because this would decrease their bioadhesive capability. Suchbioadhesive polymers may be prepared by conventional free radicalpolymerization techniques utilizing initiators such as benzoyl peroxide,azobisisobutyronitrile, and the like. Exemplary preparations of usefulbioadhesives are provided in the '697 patent.

[0040] The bioadhesive formulation may be in the form of a gel, cream,tablet, pill, capsule, suppository, film, or any other pharmaceuticallyacceptable form that adheres to the mucosa and does not wash awayeasily. Different formulations are further described in the '697 Patent,which is incorporated herein by reference.

[0041] Additionally, the additives taught in the '697 patent may bemixed in with the cross-linked polymer in the formulation for maximum ordesired efficacy of the delivery system or for the comfort of thepatient. Such additives include, for example, lubricants, plasticizingagents, preservatives, gel formers, tablet formers, pill formers,suppository formers, film formers, cream formers, disintegrating agents,coatings, binders, vehicles, coloring agents, taste and/or odorcontrolling agents, humectants, viscosity controlling agents,pH-adjusting agents, and similar agents.

[0042] The specific preparation (COL-2301) used in the studies discussedin the examples consists of the following ingredients. TABLE 1 PreferredCompositions Active Ingredient mg/g 1.0 2.0 4.0 Terbutaline (sulfate) %(w/w) 0.1% 0.2% 0.4% Purified Water 755.4 754.4 752.4 Glycerin 139.0139.0 139.0 Light liquid paraffin 42.0 42.0 42.0 Carbomer 934P 30.0 30.030.0 Polycarbophil 20.0 20.0 20.0 Methylparaben 1.8 1.8 1.8 Sorbic acid0.8 0.8 0.8 Sodium Hydroxide 0.0-2.0 0.0-2.0 0.0-2.0 LABRAFIL ® M2130 1010 10

[0043] Carbomer is a gel former, preferably Carbopol 934P, but may besubstituted by other gel formers including, but not limited to, Carbomer974P, Carbomer 980, methyl cellulose or propyl cellulose.

[0044] LABRAFIL® M2130 is a lubricant/whitening agent to providelubricity and add color to the gel; alternatives may be used, andcoloring may be left out altogether.

[0045] Glycerin is a humectant; alternative humectants include, forexample, propylene glycol or dipropylene glycol.

[0046] Preparation of the formulation involves hydration of thepolymers, separate mixing of water-soluble ingredients (the “polymerphase”) and oil-soluble ingredients (the “oil phase”), heating andmixing of the two phases, and homogenization of the mixture. Allingredients in COL-2301 are well known and readily available fromsuppliers known in the industry.

[0047] The polymer phase may generally be prepared by mixing the water(with about 3% excess volume of water to account for evaporativelosses), sorbic acid, and methylparaben together. This mixture is heatedto 75° C. The solution is cooled, generally to room temperature, andthen the polycarbophil and Carbomer are added. The polymers are hydratedby mixing for several hours, generally about 2-3 hours until a uniform,smooth, homogenous, lump-free gel-like polymer mixture is obtained. Whenthe polymers are completely hydrated, the terbutaline is added and mixedin, until a homogeneous suspension is obtained.

[0048] The oil phase is generally prepared by melting together theLABRAFIL® M2130, glycerin, and light liquid paraffin, by heating to 75to 78° C. The mixture is cooled to about 60° C., while the polymer phaseis warmed to about the same temperature. The polymer phase is then addedto the heated oil phase. The two phases are mixed thoroughly, producinga uniform, creamy white product. Sodium hydroxide is added, as needed,to produce a pH of about 2.5-4.5, generally about 4. When the mixturehas cooled, it is de-aerated.

[0049] As will be apparent to those skilled in the art, the compositionof the formulation can be varied to affect certain properties of theformulation. For example, the concentration of the bioadhesive polymercan be adjusted to provide greater or lesser bioadhesion. The viscositycan be varied by varying the pH or by changing the concentration of thepolymer or gel former. The relative concentrations of the oils comparedto the water can be varied to modulate the release rate of theterbutaline from the drug delivery system. The pH can also be varied asappropriate or to affect the release rate or bioadhesiveness of theformulation.

[0050] One of the surprising, but important aspects of the presentformulation is that it allows the drug to be administered effectivelyeven during menses. The particular bioadhesive qualities prevent thecomposition from being diluted or washed away, as would be expected withother bioadhesive preparations. This characteristic increases theutility of the present formulation.

[0051] Additionally, in light of the information disclosed in U.S. Pat.No. 5,543,150, it now appears that this bioadhesive formulation canprovide local vaginal administration of different drugs to yieldsignificant local drug levels while maintaining serum levels low enoughto avoid most undesired side effects. It was a surprising result thatthis formulation serves as an acceptable carrier for two differentactive ingredients-progesterone, and now terbutaline. Now, given itsdemonstrated flexibility and range of efficacy, it is reasonable toexpect that the bioadhesive formulation will work with other activeingredients as well.

EXAMPLES Example 1 The Pharmacokinetic Parameters of the TerbutalineComposition, A Single Dose Study

[0052] The objective of this study was to assess the pharmacokineticparameters of the terbutaline and polycarbophil composition following asingle dose regimen comparing progressively increasing concentrations.This open-label study was conducted in ten healthy female volunteerswith a mean age of 25±SD (Standard Deviation) of 3.93 years. This studyconsisted of a 30 day screening period and a 24 hour treatment periodwith a follow-up evaluation conducted two days after administration ofthe final dose. The drug was administered transvaginally at 9:00 a.m. Awash out period of at least one week as observed between each of thefour doses of the drug. All subjects were given an estro-progestativepill, to ensure that all study participants were at the same point intheir menstrual cycle. They began dosing on day 7 to 10 of their pillintake for the single dose study. Serum terbutaline concentrations wereobtained from blood samples collected predosing on the mornings oftreatment, at frequent intervals during the initial 24 hours post dose(0.5, 1, 1.5, 2, 4, 6, 8, 12, 24 hours) and at 48 hours post dose. Serumterbutaline concentrations were determined using gas chromatography-massspectrometry. Pharmacokinetic parameters were computed usingconcentration-time data for each subject following intake of the lastdose of investigational drug on the morning of study day 6. Thefollowing pharmacokinetic parameters were computed: area under the drugconcentration-time curve from time 0 to time t (AUC_(0-t)), where t isthe time of the last measurable concentration; peak drug concentration(C_(max)); time to peak drug concentration (t_(max)); steady state drugconcentration (C_(SS)); and, elimination half-life (t_(½)).

[0053] All ten subjects completed the study for the 0.1%, 0.2%, and 0.4%(w/w) concentrations. For each dose, the onset of serum terbutalineconcentrations occurred within 1 to 2 hours. (See FIG. 1 and Table 2showing terbutaline concentrations for each tested dose). Terbutalineconcentrations increased slowly reaching C_(max) after 13-14 hours andthereafter remained flat (steady state) for 24 hours with a mean steadystate concentration (C_(SS)) of approximately 300 pg/mL with the 0.4%concentration. Concentrations were still detectable for up to 48 hours(mean±SEM (Standard Error of the Mean) of 113.11±32.25 pg/mL for the0.4% concentration). Terbutaline absorption exhibited dose-dependentpharmacokinetics as reflected by the increase in AUC₀₋₄₈ values (seeTable 2 and FIG. 1) to increases in terbutaline dosing. Mean t_(½)estimates varied from 18 to 29 hours according to the dose administeredand markedly exceeded measured t_(½) after terbutaline administration byintravenous or subcutaneous routes, as had been found in the prior art.TABLE 2 Single Dose Study, Pharmacokinetic Parameters Single Dose StudyPharmacokinetic Parameters (mean ± SEM) Terbutaline Dose n C_(max)(pg/mL) T_(max) (h) C_(ss) (pg/mL) t_(1/2) (h) AUC_(0 to 48) (pg.h/mL)0.1% 10 117 ± 59  13 ± 6 56 ± 41 18 ± 12 2281 ± 1836 0.2% 10 297 ± 17013 ± 6 191 ± 108 29 ± 15 8011 ± 4699 0.4% 10 479 ± 149 14 ± 7 294 ± 11524 ± 16 11893 ± 5277 

Example 2 The Pharmacokinetic Parameters of the Terbutaline Composition,A Multiple Dose Study

[0054] The multiple dose study was an open-label study conducted in 12healthy female volunteers with a mean age±SD of 25±4.13 years. The doseused in this study was 0.4%. This study consisted of a 30 day screeningperiod, a 6 day treatment period, and a 2 day follow-up. The drug wasadministered transvaginally once daily at 9:00 a.m. All subjects weregiven an estro-progestative pill, to ensure that all study participantswere at the same place in their menstrual cycle. They began dosing onday 13 to 16 of their pill intake for the multiple dose study. Serumterbutaline concentrations were obtained from blood samples collectedpredosing on the mornings of treatment, at frequent intervals during theinitial 24 hours post-dose (0.5, 1, 1.5, 2, 4, 6, 8, 12, and 24 hours),and at 48 hours post-dose. Samples were also obtained just before eachadministration and at regular intervals after the last dose (0.5, 1,1.5, 2, 4, 6, 8, 12, and 24 hours). Serum terbutaline concentrationswere determined using gas chromatography-mass spectrometry.

[0055] Pharmacokinetic parameters were computed using concentration-timedata for each subject following intake of the last dose ofinvestigational drug on the morning of study day 6. The followingpharmacokinetic parameters were computed: area under the drugconcentration-time curve from time 0 to time t (AUC_(0-t)), where t isthe time of the last measurable concentration; peak drug concentration(C_(max)); time to peak drug concentration (t_(max)); steady state drugconcentration (C_(SS)); and, elimination half life (t_(½)). Elevensubjects completed the study, with one subject withdrawing from thestudy due to lipothymia occurring just before first dose administrationand recurring 30 minutes after the first dose. Pharmacokineticparameters are presented in FIG. 2 and Table 3. C_(max) was reachedafter approximately 9 hours (477±259 pg/mL) on day 1 and was multipliedby approximately two-fold on day 6. Moreover, it remained well below theknown threshold susceptible to trigger systemic adverse events such astachycardia and tremor, the latter reported as being approximately3,000-3,500 pg/mL. Terbutaline steady state concentration was achievedafter the first dose (mean±SEM: 287±96 pg/mL). The mean C_(SS) was 10 to15 times less than therapeutic concentrations of terbutaline forintravenous preterm labor therapy described in the prior art. SeeLyrenas, S, Grahnen A, Lindberg B. et al., Pharmacokinetics ofTerbutaline During Pregnancy, Eur. J. Clin. Pharmacol., 29:619-23(1986). Comparison of the AUC₀₋₂₄ for days 1 and 6 revealed a two-foldincrease. Mean t_(½) estimates were 51 hours on day 6. TABLE 3 MultipleDose Study, Pharmacokinetic Parameters Multiple Dose StudyPharmacokinetic Parameters (mean ± SEM) Terbutaline C_(max) T_(max)C_(ss) AUC_(0 to 48) Dose Day n (pg/mL) (h) (pg/mL) t_(½) (h) (pg ·h/ml) 0.4% 1 11 477 ± 259 9 ± 6 287 ± 96  —  6896 ± 2304 0.4% 6 11 769 ±465 9 ± 5 563 ± 339 51 ± 91 13512 ± 8135

Example 3 A Dose Comparison

[0056] Both the single and multiple dose studies discussed in thepreceding examples also evaluated the 0.8% w/w concentration. Theaverage age±SD for the single and multiple dose studies at the 0.8 dosewere 26±3.42 and 26±4.12, respectively. The pharmacokinetic parametersfrom the study follow in Tables 4 and 5. TABLE 4 Single Dose Study,Pharmacokinetic Parameters Single Dose Study Pharmacokinetic Parameters(mean ± SEM) Terbutaline Dose n C_(max) (pg/mL) T_(max) (h) C_(ss)(pg/mL) t_(1/2) (h) AUC_(0 to 48) (pg.h/mL) 0.8% 8 787 ± 434 10 ± 3 579± 300 20 ± 7 23222 ± 13530

[0057] TABLE 5 Multiple Dose Study, Pharmacokinetic Parameters MultipleDose Study Pharmacokinetic Parameters (mean ± SEM) Terbutaline C_(max)T_(max) C_(ss) AUC_(0 to 48) Dose Day n (pg/mL) (h) (pg/mL) t_(½) (h)(pg · h/ml) 0.8% 1 10  794 ± 394 11 ± 5  567 ± 322 — 13618 ± 7718  0.8%6 10 1537 ± 906  9 ± 2 1135 ± 679 19 ± 4 27246 ± 16299

[0058] As can be seen in FIGS. 3 and 4, the serum terbutaline levels inboth cases did not reach known levels for toxicity (3000 pg/ml), nor didthey even therapeutic concentrations for other conditions such as asthma(1600 pg/ml). A number of patients in the study (40%), however,experienced side effects such as tachycardia at this dose. Theoccurrence of adverse events at this dose was an unexpected result ofthe invention, as again the serum levels did not reach known levels fortoxicity. This dose can be a method of practicing the invention, but iscertainly not the most preferred embodiment.

Example 4 Human Ex Vivo Uterine Perfusion Model

[0059] This model verifies the preferential direct delivery ofterbutaline from the vagina to the uterus. In this study, uteri obtainedfrom women undergoing hysterectomies for benign diseases wereimmediately connected to an organ perfusion system in which temperature,CO₂ concentration, uterine artery pressure and flow were maintainedconstant. A perfusion model was opened without recirculation. The directtransfer of terbutaline from the vagina to the uterus was analyzed byapplying a mixture of tritiated [³H] terbutaline and unlabeledterbutaline to the cuff of vaginal tissue remaining attached to thecervix after the hysterectomy. Tritiated terbutaline was only used forautoradiography analysis of sections of uterine tissue. The experimentswere interrupted at predetermined time intervals after vaginalapplications (3 to 12 hours). At the end of the perfusion period, ³H and¹⁴C radioactivity was measured in endometrial and myometrial samples.Tritiated water and ¹⁴C dextran helped to determine that the extend ofnon-specific vagina to uterus transport (due to leaks of the system) wasless than 10%. The myometrial extraction of terbutaline and itscorresponding venous outflow during the 12 hour uterine perfusions areshown in FIG. 3 below. The ³H terbutaline started to be recovered in thevenous effluent uterine during the first 3 hours.

[0060] Terbutaline flow was maximal at the 6th-9th hour and thendecreased for up to 48 hours of perfusion. Terbutaline flow in thevenous effluent uterine is the reflection of terbutaline exiting fromthe organ. Accumulation of tritiated terbutaline was maximal in themyometrium at 12 hours of perfusion. (Mean±SD of 18.40±3.40 ng/100 mg oftissue) and decreased slowly. Significant accumulation of ³H terbutalinestill remained at 48 hours of perfusion, with 20% of the originalconcentration present.

[0061] These data demonstrate that a FIRST UTERINE PASS EFFECT® alsooccurs when terbutaline is delivered vaginally. The nature of the activeingredient and the utilized bioadhesive delivery system of the presentinvention seem even to be responsible for a more delayed and prolongeddelivery of vaginal terbutaline gel than the one described for vaginalprogesterone. Indeed, it is unexpected that the maximal myometrialconcentration of terbutaline occurred later than that for progesterone.Further, it is notable that terbutaline in the myometrium was shown tolast over 48 hours after a single vaginal application. Vaginalterbutaline gel achieves high myometrial concentrations of terbutalinerelative to its low systemic concentrations and, consequently, tomaximizes utero relaxant effects and minimizes systemic adverse effects.

[0062] Any and all publications and patent applications mentioned inthis specification are indicative of the level of skill of those skilledin the art to which this invention pertains. All publications and patentapplications are herein incorporated by reference to the same extent asif each individual publication or patent application was specificallyand individually indicated to be incorporated by reference.

[0063] Reasonable variations, such as those which would occur to askilled artisan, can be made herein without departing from the spiritand scope of the invention.

We claim:
 1. A pharmaceutical composition comprising a therapeuticallyeffective amount of a β-adrenergic agonist together with apharmaceutically acceptable bioadhesive carrier.
 2. The composition ofclaim 1 wherein the β-adrenergic agonist is terbutaline.
 3. Thecomposition of claim 2 wherein the bioadhesive carrier comprises across-linked carboxylic polymer.
 4. The composition of claim 3, whereinthe concentration of terbutaline is from 0.1 to 0.4% weight/weight. 5.The composition of claim 4, wherein the polymer is polycarbophil.
 6. Thecomposition of claim 5, wherein the β-adrenergic agonist is terbutalineand the composition is prepared so that a dosage of about 1 to 1.5 g ofcomposition will deliver from 1 to 4 mg of terbutaline.
 7. A method ofpreventing or treating dysmenorrhea comprising administering vaginallyto a host in need thereof the pharmaceutical composition of claim
 1. 8.The method of claim 7, wherein the β-adrenergic agonist is terbutalineand the dosage of composition administered contains from 1 to 4 mg ofterbutaline.
 9. The method of claim 7, wherein the composition isadministered every 12 to 48 hours during dysmenorrhea.
 10. The method ofclaim 7, wherein the composition is administered every 12 to 48 hoursbeginning one day prior to the anticipated onset of dysmenorrhea andcontinuing during dysmenorrhea.
 11. The method of claim 7, wherein thecomposition is administered every 24 hours during dysmenorrhea.
 12. Themethod of claim 7, wherein the composition is administered every 24hours beginning one day prior to the anticipated onset of dysmenorrheaand continuing during dysmenorrhea.
 13. A method of preventing ortreating premature labor comprising administering the composition ofclaim 1 vaginally, in a therapeutically effective amount.
 14. The methodof claim 13, wherein the β-adrenergic agonist is terbutaline and thedosage of composition administered contains from 1 to 4 mg ofterbutaline.
 15. The method of claim 13, wherein the composition isadministered every 12 to 48 hours to prevent or treat premature labor.16. The method of claim 13, wherein the composition is administeredevery 24 hours to prevent or treat premature labor.
 17. A pharmaceuticalcomposition for vaginal administration of a treating agent to achievelocal efficacy without detrimental blood levels of the treating agent,comprising a therapeutically effective amount of a treating agenttogether with polycarbophil.
 18. A method of vaginally administering thecomposition of claim 17, in a therapeutically effective amount.
 19. Apharmaceutical composition for vaginal administration of a treatingagent during menses, comprising polycarbophil and a therapeuticallyeffective amount of a treating agent.